Disclaimer:
The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed
literature available at the time they are written and are intended only to assist clinicians in decision-making
and to identify questions for further research. New evidence may have emerged since the time an annotation was
submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or
diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all
proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider
to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the
ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB
assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of
the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the
"Variant" column for more information about a particular variant. Each link in the "Variant" column leads to
the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually
curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these
PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding
Variant Page on the appropriate tab.

Details

†
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped
onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries
by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for
potential regulatory regions.

Note: The KCNH2 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand; therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.

The KCNH2 gene, or human Ether-a-go-go Related Gene (hERG), codes for a potassium voltage gated ion channel [Articles:14999113, 7736582]. The current through the channel is termed the rapid component of the cardiac delayed rectifier (I Kr). The gene is located on chromosome 7 and has 15 exons. Mutations and variants of KCNH2 are one cause of the congenital long QT syndrome (LQTS), a rare syndrome that carries an increased risk of cardiac arrhythmias, including the polymorphic ventricular tachycardia termed torsades de pointes (TdP), which can be fatal [Articles:17143043, 16554806]. There has also been an association between KCNH2 variants and sudden infant death syndrome (SIDS) [Article:947572]. Variants in many other genes can cause congenital LQTS (see, for example, OMIM KCNQ1, OMIM KCNE2, and OMIM SCN5A). However, the syndrome of drug-induced LQTS is most often caused by the block of the hERG channels encoded by the KCNH2 gene.[Articles:18447395, 17143043, 16554806, 12747773, 7736582]. Other mechanism for drug-associated QT prolongation and Tdp have been reported [Articles:18447395, 8873679]. In addition, other conditions, such as heart block or severe electrolyte abnormalities, can also cause QT prolongation and TdP; collectively, the drug-induced and other forms are termed the acquired LQTS (aLQTS).

For the remainder of this summary, the gene KCNH2 and the encoded protein, hERG, will be used interchangeably.

However, there are very few variants and amino acid changes that have been clearly associated with drug-induced hERG-related LQTS. For example, K897T (rs1805123) has been shown, in several studies, to be associated with longer [Articles:15746444, 14499861],or shorter QT intervals [Articles:10862094, 12829173, 19019189]. K897T was also shown to create a phosphorylation site that inhibited channel activity, independent of drug binding [Article:18791070]. But, the impact of common KCNH2 polymorphisms, including K897T as well as P967L, R1047L (rs36210421) and Q1068R were found to have no significant differences in cisapride IC50 values or Hill coefficients (compared to wild-type) for inhibition of the encoded current by the prototypical blocker cisapride [Article:14975928].

A number of studies have strongly supported the idea that variation not only in KCNH2 but also in other cardiac ion channel and associated genes may predispose to aLQTS. Yang et al [Article:11997281] found that approximately 5% to 10% of individuals with drug-induced TdP actually may have congenital LQTS with rare LQTS-associated channel mutations. This study also identified R784W (rs12720441 ) in patients with drug-associated (amiodarone) TdP [Article:11997281]. In addition, Kannankeril, et al [Article:15851285] found that quinidine prolongs terminal repolarization in family members of patients with drug-induced long QT syndrome, but not in family members of patients who safely tolerate chronic therapy with QT-prolonging drugs

Virtually all drugs that cause drug-induced QT prolongation are KCNH2/I Kr blockers [Articles:12747773, 16554806]. Eight drugs (astemizole, sertindole, terfenadine, cisapride, grepafloxacin, terodiline, lidoflazine, levomethadyl) have been removed from the market because of the risk of aLQTS and fatal TdP [Articles:15718164, 14999113]; and a ninth, droperidol, has received highly restrictive labeling [Article:14999113].

As a result of these events, testing for hERG blocking activity and subsequent evaluations for QT interval prolonging potential are routine in the pharmaceutical industry and such screening has resulted in the halting of drug development of compounds that exhibit these potentially undesirable effects. [Articles:11166255, 16554806]

The list of QT-prolonging drugs and hERG/I Kr inhibitors is large and diverse: